Compound and process for producing beta-adrenergic receptor agonist

ABSTRACT

A process is provided for preparing a compound of the formula:  
                 
 
     comprising deprotecting a compound of the formula

FIELD OF THE INVENTION

[0001] This invention relates to producing a process for making(4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenylaceticacid.

BACKGROUND OF THE INVENTION

[0002](4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenylaceticacid (herein also referred-to as “Compound I”) has the followingstructure:

[0003] A specific synthesis for compound I is disclosed in Example 1 ofInternational Patent Application PCT/IB95/00344, publishedinternationally as WO 96/35671, which designated, inter alia, the UnitedStates, which was filed in the U.S. as co-pending application Ser. No.08/945,551 on Nov. 4, 1997 and which is herein incorporated byreference.

[0004] The compound is a selective β-adrenergic receptor agonist whichhas utility for, inter alia, the treatment of hyperglycemia, obesity,intestinal motility disorders, depression, prostate disease,dyslipidemia, and airway inflammatory disorders such as asthma andobstructive lung disease. The compound is also useful for increasinglean meat deposition and/or improving the lean meat to fat ratio inedible animals such as ungulate animals and poultry. The majority ofagonist activity resides in the R-enantiomer.

SUMMARY OF THE INVENTION

[0005] This invention provides a process for preparing a compound of theformula:

[0006] comprising deprotecting a compound of the formula

[0007] wherein R² and R³ are independently C₁-C₃ alkyl or phenyl.Deprotecting in this instance thus means converting the pyrrolidinogroup to free amino. As indicated, R² and R³ can be different. It ispreferred that R² and R³ are the same.

[0008] The invention further provides a process for preparing a compoundof formula III:

[0009] wherein R¹ is C₁-C₈ alkyl,

[0010] comprising converting the pyrrolidino group in a compound offormula

[0011] wherein R² and R³ are as previously defined, to an amino (—NH₂)group. It is noted that compound III is useful as a penultimateintermediate which can be hydrolyzed by base in a reaction inert solventto make compound (I).

[0012] In another aspect, this invention provides a process forpreparing a compound of formula (I), comprising deprotecting a compoundhaving the formula

[0013] wherein R¹, R², and R³ are is as previously defined. Deprotectingin this instance means converting the western end of the molecule frompyrrolidino to amino, and converting the eastern (amide) portion, (e.g.,by hydrolysis) to the free acid.

[0014] In further aspects, as further disclosed and described below,this invention provides certain intermediates useful in the processesdescribed above.

DETAILED DESCRIPTION

[0015] The chemistry of the instant invention is disclosed as a flowchart in Scheme 1.

[0016] As illustrated, 2-amino-5-bromopyridine (5), availablecommercially from a number of suppliers including Aldrich ChemicalCompany, Inc., Milwaukee, Wis., is treated with a compound of theformula R²CO(CH₂)₂COR³, wherein R² and R³ are as previously defined,under Dean-Stark conditions to make a5-bromo-(2,5-dialkyl-pyrrol-1-yl)-pyridine (10), such as5-bromo-(2,5-dimethylpyrrol-1-yl)-pyridine (10). The reaction isconducted in any conventional reaction inert solvent, which allows waterremoval by distillation, such as toluene or ethylbenzene, or bycontacting with a conventional drying agent. Workup can be by isolationof the product under reduced pressure followed by cleanup with awater/isopropyl ether extraction system, with product being isolated, ifdesired, by evaporation to yield an oil that solidifies.

[0017] Bromide (10) can be converted to5-(2-haloacetyl2-(2,5-dimethylpyrrol-1-yl)pyridine (15), wherein X, thehalo group, is chloro or bromo, by lithium-halogen exchange of thebromide using butyllithium followed by acylation. Bromide (10) can betreated with butyllithium at reduced temperature, for example −78° C.,followed by acylation with the corresponding2-halo-N-methoxy-N-methylacetamide or α-halodimethylacetamide whilemaintaining reduced temperature, to yield α-haloketone (15). Thereaction is conducted in a suitable solvent, such as diisopropyl ether,diethyl ether, or preferably, methyl tert-butyl ether (MTBE). Theα-haloketone (15) product can be worked up conventionally, for exampleusing aqueous (e.g, 1M) hydrochloric acid, followed by separation of thephases and isolation of (15) by evaporation.

[0018] α-haloketone (15) can be used to introduce chirality into themolecule by asymmetrically reducing (15) to the corresponding chiralalcohol (35) [structure shown in left hand pathway] with a chiralpinene-derived boron reagent such as (−)-β-chlorodiisopinocampheylborane(DIP-Cl) or with alpine borane, with DIP-Cl being preferred. Thereaction can be run at reduced temperature in a solvent such as methyltert-butyl ether or, preferably, THF. Oxidative workup of theintermediate chiral alcohol to afford epoxide (20), without isolatingalcohol (35), can be effected by any of several oxidizing agents in thepresence of base, including any of hydrogen peroxide, triethylamineN-oxide, sodium percarbonate or sodium perborate in the presence of analkali metal hydroxide such as sodium hydroxide. Sodium percarbonate andsodium perborate are preferred.

[0019] Epoxide (20) can be reacted with compound (25) [structure shownin left hand pathway], an alkyl 4-(2-aminoethoxy)phenylacetamide whereinR¹ is C₁-C₈ alkyl, to form the protected intermediate (IV). A crudesolution of the epoxide, generated as described above, and the amide(25) can be combined in DMSO and heated to within the range of 60 to100° C., typically for a timespan of several hours. The product can beworked up by any convenient liquid-liquid extraction procedure (e.g.EtOAc/water) and can be further purified by acid/base extraction. Theproduct can be isolated conventionally by concentration of solvent, forexample by evaporation.

[0020] A preferred alternative procedure for preparing protectedintermediate (IV) involves making α-haloketone (15) as described aboveand conducting the chemistry alternatively illustrated (left handpathway) in Scheme 1. Chirality is introduced via an asymmetricreduction of (15), thereby producing chiral alcohol (35), by treatingketone (15) with a catalytic amount of oxazaborolidine as shown, made insitu by combining (1S,2R)-2-amino-1,2-diphenylethanol with BH₃·SMe₂ in asolvent such as THF or toluene. Alcohol (35) can then be epoxidized byadding base to the reaction medium to produce epoxide (20) (not shown),which can then be reacted directly with intermediate amide (25) toproduce protected alcohol (IV). Epoxide (20), not shown in the leftsynthesis branch of Scheme 1, was not isolated. Generally a solvent suchas DMSO or THF is employed and the reaction medium is heated to atemperature between 60 and 100° C., typically 80-90° C.

[0021] Those skilled in the art will appreciate that the asymmetricchiral reduction of α-chloroketone (15) can be conducted using a numberof additional chiral reductants, other than those specifically disclosedand illustrated, which are known and/or commercially available.

[0022] The preparation of amide (25) has been described in InternationalPatent Publication Number WO 98/21184, herein incorporated by reference,and such compounds are disclosed therein as compounds of formula XVI.Such compounds may be prepared as set forth in the Examples below. Forexample, the amide of formula (25) wherein R⁴ is methyl is prepared asset forth in Preparation I below. Other such C₁-C₈ alkyl amides (25) maybe prepared by methods analogous thereto.

[0023] The final product, compound (I), is made as shown in Scheme 2, bydeprotection of compound (IV).

[0024] The compound (IV) is treated with a base, preferably an alkalimetal hydroxide, and with hydroxylamine hydrochloride to deprotect atboth the eastern and western ends of the molecule. Thus alcohol (IV) canproceed through compound II or compound III enroute to forming thedesired final product. The particular sequence of deprotection is notconsidered critical. Alcohol (IV) can first be treated with base tohydrolyze the eastern (amide) portion of the molecule to producepenultimate intermediate (II). Alternatively, alcohol (IV) can first bedeprotected at the western end of the molecule by converting thepyrrolidino group to free amino, thereby producing penultimateintermediate (III). The final product, compound (I), can be isolated ina conventional manner by neutralizing the basic solution andprecipitating the zwitterion. Depending on the level of inorganic saltsin the material, it may be necessary to rework the product. This can beeffected by rebasicifying in aqueous NaOH, filtering, neutralizing toprecipitate zwitterion, and repulping in water or a lower alcohol,preferably ethyl alcohol.

[0025] Conventional methods and techniques of purification andseparation known to those skilled in the art may be used to isolate thecompounds of this invention. Such techniques include all types ofchromatography, including but not limited to high performance liquidchromatography, column chromatography using common adsorbents such assilica gel, thin layer chromatography and the like; recrystallization;and differential (i.e., liquid-liquid) extraction techniques.

[0026] In the reaction schemes discussed herein, compounds (II), (IV),(10), (15), (20), and (35) are believed to be novel, and each ispresented as an additional novel feature of the invention.

[0027] The invention is further disclosed and described by the followingexamples, which are for purposes of illustration only, not limitation.Reference to “HPLC” means reverse phase HPLC using a Symmetry™ C8 column(Waters Corporation, Milford, Mass.) with an isocratic solventconsisting of various proportions, depending on the analyte, ofacetonitrile and pH 3.2 phosphoric acid/triethylamine buffer, using UVdetection. The following conventional abbreviations have been employedherein: h—hours; m.p.—melting point; MTBE—methyl tert-butyl ether;IPE—isopropyl ether; N—normal; M—molar; mol—moles; mL—milliliter;g—grams; THF—tetrahydrofuran; temp.—temperature; HPLC—high performanceliquid chromatography; rt—room temperature; DMSO—dimethylsulfoxide;EtOAc—ethyl acetate; Me—methyl; Bu—butyl; Ph—phenyl; MeOH—methanol;EtOH—ethanol; NEt₃—triethylamine;

EXAMPLE 1 5-Bromo-2-(2,5-dimethylpyrrol-1-yl)-pyridine

[0028]

[0029] To a solution of 2-amino-5-bromopyridine (89.87 g, 0.5194 mol) intoluene (500 mL) was added 2,5-hexanedione (85.0 mL, 0.724 mol). Thereaction flask was equipped with a Dean-Stark apparatus and the solutionheated to reflux for 14 h. The cooled reaction solution was extractedwith H₂O (2×200 mL). The organic layer was added directly to a plug ofSiO₂ 3“1×2”w and eluted with toluene (250 mL). This treatment removes asignificant amount of color from the crude product. The resulting eluentwas concentrated to a light amber oil, which solidified upon cooling toprovide 128.76 g (99%) of the title compound.

[0030]¹H NMR (400 MHz, CDCl₃): 2.13 (s, 6), 5.90 (s, 2), 7.12 (d, 1,J=8.3), 7.93 (dd, 1, J=2.5, 8.3), 8.65 (d, J=2.5).

[0031]¹³C NMR (100 MHz, CDCl₃): 13.21, 107.41, 118.92, 123.01, 128.60,140.51, 150.43, 150.71.

[0032] Anal. Calcd for C₁₁H₁₁N₂Br C, 52.61; H, 4.42; N, 11.16. Found: C,52.68; H, 4.28; N, 10.99.

EXAMPLE 2 5-(2-Chloroacetyl)-2-(2,5-dimethylpyrrol-1-yl)pyridine

[0033]

[0034] A solution of the compound made as in Example 1 (100.00 g, 0.3982mol) in MTBE (1.5 L) was cooled to −78° C. To the solution was addedBuLi (175 mL, 2.5 M in hexanes, 0.4375 mol) over 15 min, causing a risein internal temperature from −78° C. to −70° C. After 10 minutes, asolution of 2-chloro-N-methoxy-N-methylacetamide (63.10 g, 0.4587 mol)in MTBE (200 mL) was added over 10 min, causing a rise in internaltemperature from −78° C. to −65° C. After an additional 20 min, 1M HCl(1 L) was added, and the cooling bath removed. The mixture was stirredvigorously for 2 h while warming to rt, and then the layers separated.The aq. layer was extracted with MTBE (400 mL), and the combined organiclayers were extracted with 400 mL brine (containing 30 mL 12.5MNaOH-this wash serves to free base any protonated pyridine). The org.layer was dried with MgSO₄, filtered and concentrated to provide crudetitle compound as a red oil. To the crude oil was added hexanes (500 mL)and the mixture stirred vigorously overnight. The mixture thus obtainedwas filtered, and the solids rinsed with hexanes (2×100 mL) to provide81.32 g (82%) of the title compound as a tan, slightly sticky powder.This material should be stored cold, as prolonged storage at rt willcause darkening and impurity buildup.

[0035]¹H NMR (300 MHz, CDCl₃): 2.18 (s, 6), 4.69 (s, 2), 5.93 (s, 2),7.33 (ap. d, 1, J=8.3), 8.36 (ddd, 1, J=1.3, 2.6, 8.5), 9.11-9.13 (m,1).

[0036]¹³C NMR (100 MHz, CDCl₃): 13.65, 45.48, 108.59, 121.16, 127.70,128.88, 138.07, 149.78, 155.67, 189.41.

[0037] Anal. Calcd for C₁₃H₁₃N₂OCl: C, 62.78; H, 5.27; N, 11.26. Found:C, 62.75; H, 5.11; N, 11.27.

[0038] Mass Spec: AP+=249.1, AP−=247.2

EXAMPLE 3 (R)-2-(2,5-dimethylpyrrol-1-yl)-5-oxiranylpyridine

[0039]

[0040] To a N₂ purged flask was added (−)-DIP-Cl[(−)-β-chlorodiisopino-campheylborane, 75.90 g, 0.2366 mol] which wasrinsed into the flask with MTBE (50 mL). To the solution was added THF(112.5 mL), and the mixture cooled to approx. −30° C. A solution ofcompound made as in Example 2 (45.0 g, 0.181 mol) in THF (67.5 mL) wasadded dropwise over 10 min, causing the internal temp. to reach amaximum of −19° C. The reaction was held between −30° C. and −23° C. for6 h, upon which HPLC analysis showed complete conversion to(R)-5-(2-chloro-1-hydroxyethyl)-2-(2,5-dimethylpyrrol-1-yl)-5-(2chloro-1-hydroxyethyl)pyridine(chiral HPLC of aliquot shows 93% ee). To the solution was addedNaBO₃·4H₂O (27.8 g, 0.181 mol) followed by MTBE (175 mL). The mixturewas stirred at rt overnight. To the reaction mixture was added 2N NaOH(675 mL) and the mixture stirred at rt for 6 h. HPLC analysis showedcomplete conversion of the chiral alcohol to the title epoxide. Thelayers were separated, and the aqueous layer extracted with MTBE (560mL). The combined organic layers were extracted with 1N NaOH (225 mL)and brine (225 mL). The organic solution was dried (MgSO4), filtered,and concentrated to a thick oil to provide 82.9 g of crude epoxide whichwas contaminated with large amounts of pinene derived material. Thecrude material was used in Example 4 without further purification.

[0041]¹H NMR (400 MHz, CDCl₃): 2.11 (s, 6), 2.90 (dd, 1, J=2.6, 5.3),3.24 (dd, 1, J=4.0, 5.3), 3.96 (dd, 1, J=2.5, 4.0),5.89 (s, 2), 7.20 (d,1, J=8.1), 7.66 (dd, 1, J=2.5, 8.3), 8.56 (d, 1, J=2.5).

EXAMPLE 4 N-methyl(4-(2-(2-(6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl)2(R)-hydroxyethylamino)ethoxy)phen-1-yl)acetamide

[0042]

[0043] To a crude solution of epoxide produced as in Example 3 (74.6 gmixture, synthesized from 0.163 mol of the ketone produced as in Example2) in DMSO (140 mL) was added Methyl 4-(2-aminoethoxy)phenylacetamide(68.35 g, 0.3282 mol). The mixture was heated in an 85° C. bath for 8.5h. Heating was discontinued, and the solution allowed to cool and stirat rt overnight. The mixture was added to 0.5 M HCl (2.8 L), whichcaused a gum to separate out. The solution was extracted withdiethylether (3×1 L) and the ether washes discarded. The aqueous layerwas decanted from the gum that settled out, and 1M NaOH (2.1 L) wasadded. The aq. layer was extracted with EtOAc (2×1.4 L), the combinedorganic layers extracted with brine (500 mL) and dried over K₂CO₃. Thesolution was filtered and concentrated to an oil, which solidified to atacky solid upon storage to provide 43.38 g (63% yield, calculated onthe crude bromide (10) of Example 1 which was treated as in Examples 2and 3 without purification) of title compound which was sufficientlypure to carry forward in the synthesis. A small portion was purified bySiO₂ chromatography (MeOH/EtOAc/NEt₃) to provide an analytically puresample.

[0044]¹H NMR (300 MHz, CDCl₃): 2.14.(s, 6), 2.77 (d, 3, J=4.8), 2.84(dd, 1, J=9.5, 12.2), 3.07-3.21 (m, 3), 3.54 (s, 2), 4.13 (t, 2, J=5.0),4.84 (dd, 1, J=3.3, 9.3), 5.47 (br s, 1), 5.92 (s, 2), 6.93 (d, 2,J=8.7), 7.20 (d, 2, J=8.7), 7.24 (d, 1, J=8.1), 7.91 (dd, 1, J=2.3,8.1), 8.60 (d, 1, J=2.2).

[0045]¹³C NMR (100 MHz, CDCl₃): 13.15, 26.46, 42.70, 48.34, 56.69,67.36, 69.37, 106.87, 114.96, 121.67, 127.34, 128.59, 130.67, 135.76,136.68, 147.22, 151.36, 157.96, 172.06.

[0046] Anal. Calcd for C₂₄H₃₀N₄O₃: C, 68.22; H, 7.16; N, 13.26. Found:C, 67.82; H, 7.39; N, 13.03.

EXAMPLE 5(4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)-phenylaceticacid

[0047]

[0048] In a 200 mL flask, 40 mL abs. EtOH was added to the compoundproduced as in Example 4 (11.01 g, 26.06 mmol). The solution was heatedup to 70° C. until all the solids had dissolved (30 min). To thesolution was added 1.6M NaOH (50 mL), and the bath temperature wasraised to 100° C. After 44 hours, HPLC analysis showed only 1.2%starting material remaining. The solution was concentrated to ½ volumeby continued heating at 100° C. without condenser, followed byconcentration of the remainder under reduced pressure (bath temp=50° C.)to a fluid brown oil. The crude residue was taken up in abs. EtOH (100mL) and heated to 80° C. To the hot solution was added hydroxlyaminehydrochloride (9.06 g, 0.130 mol) and heating continuted overnight.After a total heating time of 17.5 h, the solution was cooled to rt. Theheterogenous solution was filtered, and the solids rinsed with EtOH (25mL) to provide 9.97 g of crude title compound. To the crude material wasadded H₂O (50 mL) and NaOH (1.72 g) causing most of the solids todissolve. The solution was heated up to 75° C. for 20 min, and thesolution filtered through a scintered glass frit while hot to remove avery small quantity of insoluble sediment. The solution was cooled tort, and 6M HCl was added dropwise to reduce the pH to ˜7, after whichstirring was continued for 30 min (note: solids began to come out ofsolution at pH=9.8). The solids were filtered and rinsed with water(2×10-15 mL). The purified title compound was air dried followed bydrying under high vacuum to provide 4.58 g (53%) of product which waspure by HPLC and ¹H NMR analysis.

EXAMPLE 6(R)-5-(2-chloro-1-hydroxyethyl)-2-(2,5-dimethylpyrrol-1-yl)-5-(2-chloro-1-hydroxyethyl)pyridine

[0049]

[0050] To a solution of (1S,2R)-2-amino-1,2-diphenylethanol (0.2429 g,1.139 mmol) in THF (75 mL) was added BH₃·SMe₂ (˜10.0 M, 3.80 mL). Thissolution was allowed to stir at rt for 15 h during which time hyrdogenis evolved. To the catalyst solution was added5-(2chloroacetyl)-2-(2,5-dimethylpyrrol-1-yl)-pyridine (5.5134 g, 22.168mmol), in THF (10 mL) via syringe pump over 3 h. After an additional 3h, the reaction was quenched by the slow addition of water (15 mL ),causing slow hydrogen evolution. After 1 h from water addition, thereaction solution was added to diisopropylether (50 mL), EtOAc (50 mL),and 2N HCl (200 mL) and stirred well for 15 min. The phases wereseparated and the aqueous phase extracted with EtOAc (150 mL). Thecombined organic phases were further extracted with brine (125 mL)containing 12.5 M NaOH soln (1.5 mL). The solution was dried (MgSO₄),filtered and concentrated to provide 5.27 g (95%) of crude product.Chiral HPLC (Chiracel OG column, Daicel Corporation, with UV detection)showed this material to be a 91.8:8.2 mixture of desired (R) toundesired (S) enantiomers. The crude was crystallized from EtOAc/hexanesproviding two crops of material, totalling 3.7098 g (67%) of purematerial that was a 97.5:2.5 mixture of enantiomers.

[0051]¹H NMR (400 MHz, CDCl₃): 2.12 (s, 6), 2.85 (d, 1, J=3.4), 3.7 (dd,1, J=8.6, 11.3), 3.83 (dd, 1, J=3.6, 11.3), 5.02 (ddd, 1, J=3.4, 3.4,8.3), 5.89 (s, 2), 7.23 (d, 1, J=9.2), 7.88 (dd, 1, J=2.6, 8.3), 8.60(d, 1, J=2.4).

[0052]¹³C NMR (100 MHz, CDCl₃): 13.11, 50.00, 71.06, 107.16, 121.92,128.68, 135.18, 136.37, 147.34, 151.65.

[0053] AP+=251.1

EXAMPLE 7 N-methyl(4-(2-(2-(6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phen-1-yl)acetate

[0054]

[0055] To a solution of compound produced as in Example 6 (9.99 g, 39.8mmol) in DMSO (80 mL) was added methyl 4-(2-aminoethoxy)phenylacetamide(16.23 g, 77.93 mmol) followed by KOt-Bu (4.49 g, 40.0 mmol). Themixture was heated in an 80° C. bath for 20 h. After cooling, themixture was added to water (300 mL) and EtOAc (300 mL). The phases wereseparated and the organic layer further extracted with water (2×200 mL).The organic phase was extracted with brine, dried (K₂CO₃), filtered andconcentrated to provide 13.93 g (83%) of title compound as a hard yellowsolid.

[0056]¹H NMR (300 MHz, CDCl₃): 2.14 (s, 6), 2.77 (d, 3, J=4.8), 2.84(dd, 1, J=9.5, 12.2), 3.07-3.21 (m, 3), 3.54 (s, 2), 4.13 (t, 2, J=5.0),4.84 (dd, 1, J=3.3, 9.3), 5.47 (br s, 1), 5.92 (s, 2), 6.93 (d, 2,J=8.7), 7.20 (d, 2, J=8.7), 7.24 (d, 1, J=8.1), 7.91 (dd, 1, J=2.3,8.1), 8.60 (d, 1, J=2.2).

[0057]¹³C NMR (100 MHz, CDCl₃): 13.15, 26.46, 42.70, 48.34, 56.69,67.36, 69.37, 106.87, 114.96, 121.67, 127.34, 128.59, 130.67, 135.76,136.68, 147.22, 151.36, 157.96, 172.06.

[0058] Anal. Calcd for C₂₄H₃₀N₄O₃: C, 68.22; H, 7.16; N, 13.26. Found:C, 67.82; H, 7.39; N, 13.03.

PREPARATION 1

[0059]

Methyl 4-(2-aminoethoxy)phenylacetamide

[0060] Methyl 4-2-(N-benzyloxycarbonylamino)ethoxy)phenylacetamide (18.4kg, 53.73 mol) and 1.84 kg 10% palladium on carbon (50% H₂O wet) weresuspended in 276 L of methanol under nitrogen, and the reaction vesselpressurized to 50 psig with hydrogen gas. This H₂ pressure wasmaintained by additional charges of H₂ until there was no further uptakeof H₂ (approx. 20 hours) and the reaction was complete by thin layerchromatography. After purging the vessel with N₂, the mixture was heatedto 45° C. and filtered at this temperature through Celite®. The solventwas displaced with toluene until a final volume of 30 L was achieved.After cooling to 5° C. the resulting solids were filtered off, washedwith cold toluene, and vacuum dried to give the title compound (9.95 kg,88.9% of theory). NMR (300 MHz, d₆-DMSO): δ=7.99-7.57 (m, 1H), 7.20-7.10(d, 2H), 6.90-6.80 (d, 2H), 3.93-3.83 (m, 2H), 3.30 (s, 2H), 3.00-2.62(m, 4H), 2.57 (d, 2H).

What is claimed is:
 1. A process for preparing a compound of theformula:

comprising deprotecting a compound of the formula (II)

wherein R² and R³ are independently C₁-C₃ alkyl or phenyl.
 2. A processfor preparing a compound of formula III:

wherein R¹ is C₁-C₈ alkyl, comprising converting the pyrrolidino groupin a compound of formula

wherein R² and R³ are independently C₁-C₃ alkyl or phenyl, to an aminogroup.
 3. A process for preparing a compound of formula (I),

comprising deprotecting a compound having the formula

wherein R¹ is C₁-C₈ alkyl, and R² and R³ are independently C₁-C₃ alkylor phenyl.
 4. A compound having the formula

wherein R² and R³ are independently C₁-C₃ alkyl or phenyl.
 5. A compoundhaving the formula

wherein R¹ is C₁-C₈ alkyl, and R² and R³ are independently C₁-C₃ alkylor phenyl.
 6. A compound having the formula

wherein R² and R³ are independently C₁ -C₃ alkyl or phenyl.
 7. Acompound having the formula

wherein R² and R³ are independently C₁-C₃ alkyl or phenyl and X is Cl orBr.
 8. A compound as defined in claim 7, wherein X is Cl and R² and R³are methyl.
 9. A compound having the formula

wherein R² and R³ are independently C₁-C₃ alkyl or phenyl and X is Cl orBr.
 10. A compound as defined in claim 9, wherein X is Cl and R² and R³are methyl.
 11. A compound having the formula

wherein R² and R³ are independently C₁-C₃ alkyl or phenyl.